A major characteristic of Alzheimer's Disease (Senile Dementia, SDAT) is a marked central cholinergic dysfunction. This cholinergic deficit has been reported to correlate with cognitive impairment (P. T. Francis et al, New Engl. J. Med., 1985, 313, 7). Various attempts to increase central cholinergic activity and thereby reverse the cognitive deficits have, to date, met with only limited success.
There is some evidence that use of the alkaloid physostigmine can, in some cases, be marginally beneficial, but the use of this compound in the clinic is compromised by a low therapeutic ratio, a short half-life and poor bioavailability. The cholinesterase inhibitor, 9-amino-1,2,3,4-tetrahydroacridine (THA) has been reported to be of therapeutic value in the treatment of a small group of patients with SDAT (W. K. Summers et al, New Engl. J. Med., 1986, 315, 1241). Further clinical trials of THA have produced some encouraging results but have been hampered by the association of this drug with certain toxic side effects.
Other compounds structurally related to either physostigmine or THA have been reported and are the subject of ongoing investigations.
There remains an urgent need for a safe and clinically effective drug for the symptomatic treatment of Alzheimer's Disease and related conditions.
A compound structurally similar to the compounds of the present invention, namely 1-[1-(4-benzyl-piperazinyl)methyl]isatin, is disclosed in Chemical Abstracts 98 (3):16650w referring to Boll Chim. Farm., 1992, 121 (5), pp. 221-9. Said compound is said to have pharmacological activity.
Japanese Patent Application No. 138443/86 (Publication No. KOKAI JP 62-294654A2) discloses 1-[2-(4-benzyl-piperazinyl)ethyl]isatin as an intermediate for the synthesis of isatin derivatives which are useful as an agent for treating gastric or duodenal ulcer or mammals including human beings. Said single compound is deleted from the scope of the present invention by a disclosure in claim 1.
Furthermore, European Patent Application EP 0 010 398 relates to isatin derivatives useful for treating allergic symptoms. Among all specific compounds disclosed therein is only one falling within the general formula I of the compounds of the present invention, namely 1-[3-{4-(4-chlorobenzyl)-1-piperazinyl}propyl[-isatin. Said single compound is deleted from the scope of the present invention by a disclosure in claim 1 as well.